The overall goal of this project is to discover prototype lead compounds for development of new treatments for the major AIDS- and cancer-related disseminated fungal infections. Our approach is to evaluate previously unexamined and unique sources of natural products for in vitro activity against specific fungal pathogens and for their ability to reverse resistance to existing antifungal drugs, fractionate active extracts to isolate and identify pure active compounds, and determine the physicochemical properties, mechanisms of action, and toxicological profiles of the isolated active compounds. The specific aims of this proposal are: 1) access a diverse and unique repository of extracts of plants, microbes, and invertebrate animals and prepare samples compatible with biological assays; 2) evaluate in vitro antifungal activity of the extracts for activity against Cryptococcus neoformans, Candida albicans, Candida glabrata, Candida kruseii and Aspergillus fumigatus, and for reversal of resistance to clinically available antifungal drugs; 3) isolate, elucidate the structures, and characterize the pharmaceutical properties of the active constituents; 4) characterize the biological properties of the active compounds using functional genomics, known antifungal enzymatic targets, and mammalian toxicological predictors. Successful completion of the proposed work will yield new prototype lead compounds that will serve as templates for development of new classes of antifungal agents, as templates for the development of new drugs to be used in combination with existing antifungal agents to reverse resistance to these agents, and as probes to identify novel mechanisms of action that can be exploited in the future search for other new derivatives.